Concussions are the leading cause of brain damage in sports, particularly in American football. Estimates of the frequency of concussions among football players suggest that up to 40% of participants experience a concussion on an annual basis, the majority of these going unreported. Today, concussions are confirmed or ruled out based on behavioral correlates (Immediate Post-Concussion Assessment, ImPACT and Cognitive Testing) and without the aid of standardized laboratory testing. As a result, the diagnosis of concussion remains challenging and subjective. In addition, detailed neurological testing may be delayed for several days after the event, creating uncertainty and potential risk. Concussions, or traumatic brain injury (TBI) in general, are associated with a rapid loss of cerebrovascular (blood-brain barrier, BBB) integrity followed by the development of brain damage. It is therefore significant to detect early BBB changes to predict development of post-concussion brain damage. S100B has emerged as a candidate peripheral biomarker of BBB permeability. Elevation of S100B serum levels reflect the presence of a damaged BBB and may predict brain injury. We obtained preliminary results measuring serum S100B in a cohort of college team players. S100B levels were measured prior to, immediately after and one day post-game. Average S100B levels immediately after the game were significantly higher than baseline in those players whose position predicts highest likelihood of head-to- head impact. The main goal of this R21 is to validate the use of surrogate serum markers of occult concussion in football. We will compare serum marker to accepted means of concussion testing (e.g., SCAT2) and to imaging data (DTI) obtained in selected players. A blood test could have a diagnostic value influencing the treating physician's recommendation for return to play and providing indication of potential long-term pathological brain changes. PUBLIC HEALTH RELEVANCE: Concussions are common events in sports. Concussions occur most commonly in collision sports with football being one of the highest risk activities. The Center of Disease Control estimates that approximately 300,000 concussions occur annually in the United States, the majority occurring in high school and college football players. Estimates of the frequency of concussions among these athletes suggest that up to 40% of football participants suffer a concussion on an annual basis, the majority of these going unreported. We propose to validate the use of blood markers of concussion of sufficient sensitivity to unveil occult, hidden and often undiagnosed brain injuries.